Ring-opening metathesis phase-trafficking (ROMpt) synthesis: multistep synthesis on soluble ROM supports.

Article abstract of DOI:10.1021/ol0270327

The use of ring-opening metathesis (ROM) oligomers as soluble supports for a multistep reaction sequence is described. A Mitsunobu reaction followed by an in situ ROMP-mediated phase-trafficking purification is utilized to generate soluble ROM oligomers t

Full text of DOI:10.1021/ol0270327

ORGANIC
LETTERS
2003
Vol. 5, No. 1
15-18
Ring-Opening Metathesis
Phase-Trafficking (ROMpt) Synthesis:
Multistep Synthesis on Soluble ROM
Supports
,‡
Andrew M. Harned,† Shubhasish Mukherjee,† Daniel L. Flynn,* and
,†
Paul R. Hanson*
Department of Chemistry, UniVersity of Kansas, 1251 Wescoe Hall DriVe,
Lawrence, Kansas 66045-7582, and Deciphera Pharmaceuticals, Inc.,
3 Great Rock Circle, Natick, Massachusetts 01760
dflynn@deciphera.com
Received October 4, 2002
ABSTRACT
The use of ring-opening metathesis (ROM) oligomers as soluble supports for a multistep reaction sequence is described. A Mitsunobu reaction
followed by an in situ ROMP-mediated phase-trafficking purification is utilized to generate soluble ROM oligomers that are isolated via precipitation
with methanol. Once formed, the ROM oligomers serve as soluble supports for further solution-phase reactions, including a ring-closing
metathesis. After each step, the support-bound products are isolated by precipitation with a suitable solvent.
The development of new technologies to eliminate or lessen
the need for chromatographic separation of mixtures is of
continued interest in the field of synthetic organic chemistry1
and combinatorial chemistry.2 Over the past 40 years, the
use of resin-bound supports and reagents has dominated the
literature with great success. Although very powerful,
limitations with regard to reaction kinetics and load capacity
have led to the emergence of alternative approaches. Among
these, organic soluble polymer supports and reagents3 are
attractive substitutes because they allow multistep syntheses
to proceed in the solution phase but still offer the convenience
of easy product isolation. This is achieved by precipitation
and filtration of the support-bound product. However, these
systems have traditionally suffered from decreased load
capacity. To address this issue, new polymeric systems have
emerged. Among these, dendritic4 and ring-opening meth-
athesis (ROM)-derived polymers5 have recently been em-
ployed. We now report the first use of high-load ROM
† University of Kansas.
‡ Deciphera Pharmaceuticals, Inc.
(1) Reviews: (a) Ley, S. V.; Baxendale, I. R.; Bream, R. N.; Jackson,
P. S.; Leach, A. G.; Longbottom, D. A.; Nesi, M.; Scott, J. S.; Storer, R.
I.; Taylor, S. J. J. Chem. Soc., Perkin Trans. 1 2000, 3815-4195. (b) Hall,
D. G.; Manku, S.; Wang, F. J. Comb. Chem. 2001, 3, 125-150.
(2) (a) A Practical Guide to Combinatorial Chemistry; Czarnik, A. W.,
DeWitt, S. H., Eds.; American Chemical Society: Washington, DC, 1997.
(b) Bunin, B. A. The Combinatorial Index; Academic Press: New York,
1998. (c) Combinatorial Chemistry: A Practical Approach; Fenniri, H.,
Ed.; Oxford University Press: New York, 2000; The Practical Approach
Series 233.
(3) Review: (a) Gravert, D. J.; Janda, K. D. Chem. ReV. 1997, 97, 489-
509. (b) Toy, P. H.; Janda, K. D. Acc. Chem. Res. 2000, 33, 546-554. (c)
Dickerson, T. J.; Reed, N. N.; Janda, K. D. Chem. ReV. 2002, 102, 3325-
3344. (d) ROM polymers as soluble catalysts: Bolm, C.; Dinter, C. L.;
Seger, A.; Ho¨cker, H.; Brozio, J. J. Org. Chem. 1999, 64, 5730-5731.
(4) (a) Review: Haag, R. Chem. Eur. J. 2001, 7, 327-335. (b) Haag,
R.; Sunder, A.; Hebel, A.; Roller, S. J. Comb. Chem. 2002, 4, 112-119.
10.1021/ol0270327 CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/10/2002

Scheme 1a
a Reagents and conditions: (a) (i) ClSO2NCO, CH2Cl2, 0 °C; (ii) amino ester, Et3N, CH2Cl2, 82-96%. (b) 5 mol %
(IMesH2)(PCy3)(Cl)2RudCHPh, CH2Cl2, reflux. (c) Allyl bromide, K2CO3, NaI, DMF, 50 °C. (d) (i) Cinnamyl alcohol, PPh3, DIAD, THF,
rt; (ii) 5 mol % (IMesH2)(PCy3)(Cl)2RudCHPh, CH2Cl2, reflux; (iii) EtOCHdCH2; (iv) MeOH and then filter. (e) 10 mol %
(PCy3)2(Cl)2RudCHPh, CH2Cl2, 50 °C. (f) 1:1 TFA/CH2Cl2, 49-53% over four steps.
oligomers as soluble supports for a multistep synthesis to
produce a series of unsymmetric sulfamide peptidomimetics.
The utility of ROM supports in combinatorial chemistry
was first reported by Barrett and co-workers through the
development of ROMPgel reagents6 and an “impurity anni-
hilation” reagent.7 Recently, Enholm has used ROM oligo-
mers as soluble supports for single-step free radical reac-
tions.5 We have since reported the use of capture-ROMP-
release8 and ROMP scavenging9 as alternative ROMP-based
techniques that exploit organic-soluble polymers.
We have recently reported the synthesis and ROM
polymerization of various amino acid-derived sulfonamide
monomers.10 During the course of this work, we envisioned
that norbornenyl-functionalized substrates could provide a
manifold for accomplishing (1) functional group protection
via a norbornenyl-tagged Wang-like protecting group (NWPG);
(2) phase-trafficking purification; (3) mid-stage morphing
of synthesis onto soluble supports; and (4) Wang-sensitive
TFA release of final products. This 4-fold utilization of nor-
bornenyl-tagged chemistry is termed ring-opening metathesis
phase-trafficking11 (ROMpt). After each step, the ROM
oligomer is isolated from reaction impurities, simply by
precipitation with a suitable agent, i.e., one that reaction
impurities are soluble in. Once isolated, the oligomers can
be redissolved in typical reaction solvents to allow further
functionalization. This paper describes our initial results of
this 4-fold ROMpt strategy.
We initially chose to apply monomer 112,13 (Scheme 1) to
our reported synthesis of cyclic sulfamide peptidomimetics.14
NWPG 1 was reacted with chlorosulfonyl isocyanate fol-
lowed by coupling with valine methyl ester. The NWPG-
protected sulfamoyl carbamate 2b was then polymerized with
5 mol % (IMesH2)(PCy3)(Cl)2RudCHPh. Unfortunately, the
resulting oligomer (20-mer of 2) was not soluble in CH2Cl2.
However, it was sufficiently soluble in DMF to allow for
subsequent bis-allylation resulting in the production of 4e,
which was isolated by precipitation with water in order to
remove the DMF and inorganic salts. The CH2Cl2-soluble
oligomer 4e was then treated with 10 mol % Grubbs
benzylidene catalyst to produce 5b. Cyclic sulfamide 6b was
then cleaved from the support with 1:1 TFA/CH2Cl2. While
we were pleased with the success of this ROM-supported
RCM sequence, we felt that the narrow solubility profile of
the oligomer produced from 2b warranted a change in
strategy. We felt that employing a Mitsunobu reaction and
a subsequent ROMP-mediated phase-trafficking purification
would allow the Mitsunobu products to be formed and
isolated on the ROM-polymer phase, thus avoiding the
generation of an oligomer containing two hydrogen bond
donors. Additionally, in order to carry out such a protocol,
it would be necessary to utilize a phenyl-protected olefin,
which we have previously shown to be compatible with
ROM polymerization protocols.8
To this end (Scheme 1), sulfamoyl carbamates 2 were
reacted with cinnamyl alcohol under Mitsunobu conditions.
The norbornenyl-tagged products were then induced to
undergo phase-trafficking purification by in situ polymeri-
(5) (a) Enholm, E. J.; Gallagher, M. E. Org. Lett. 2001, 3, 3397-3399.
(b) Enholm, E. J.; Cottone, J. S. Org. Lett. 2001, 3, 3959-3962.
(6) Review: Barrett, A. G. M.; Hopkins, B. T.; Ko¨bberling, J. Chem.
ReV. 2002, 102, 3301-3324.
(7) Barrett, A. G. M.; Roberts, R. S.; Schro¨der, J. Org. Lett. 2000, 2,
2999-3001.
(12) Monomer (()-1 was prepared as an ∼8:1 mixture of endo/exo
diastereomers that were carried through as a mixture for ease of use.
(13) Monomer (()-1 is prepared on a multigram scale in five steps from
styrene sulfonyl chloride. The only chromatography required in this synthesis
is the removal of dicyclopentadiene from the Diels-Alder adduct and the
removal of any aluminum salts from 1. In both cases, the careful collection
of fractions is not necessary. For more details, see Supporting Information.
(14) Dougherty, J. M.; Probst, D. A.; Robinson, R. E.; Moore, J. D.;
Klein, T. A.; Snelgrove, K. A.; Hanson, P. R. Tetrahedron 2000, 56, 9781-
9790.
(8) Harned, A. M.; Hanson, P. R. Org. Lett. 2002, 4, 1007-1010.
(9) Moore, J. D.; Harned, A. M.; Henle, J.; Flynn, D. L.; Hanson, P. R.
Org. Lett. 2002, 4, 1847-1849.
(10) Wanner, J.; Harned, A. M.; Probst, D. A.; Poon, K. W. C.; Klein,
T. A.; Snelgrove, K. A.; Hanson, P. R. Tetrahedron Lett. 2002, 43, 917-
921.
(11) For a review on phase-trafficking, see: Flynn, D. L. Med. Res. ReV.
1999, 19, 408-431.
16
Org. Lett., Vol. 5, No. 1, 2003

zation mediated by the second generation Grubbs catalyst.8
The crude reaction mixtures were poured into methanol to
precipitate oligomers 3 away from the Mitsunobu byproducts,
thus avoiding the tedious separation process often associated
with the Mitsunobu reaction. Oligomers 3 were then utilized
as organic-soluble polymer supports in subsequent steps.
Allylation gave rise to diene intermediates 4, which were
subjected to RCM conditions to give cyclic sulfamides 5.
Intermediates 4 and 5 were easily purified and isolated by
pouring the crude reaction mixtures into water or methanol,
respectively.
Wang-like tethered RCM intermediates 5 were then treated
with 1:1 TFA/CH2Cl2 to mediate release of the final products
from the soluble support. The spent oligomers were precipi-
tated with MeOH and filtered away from cleaved products
6a-d. The crude isolated products were then passed through
a short plug of silica, eluting with 1:1 hexane/EtOAc. All
final products 6a-d were isolated in >90% purity as judged
by H NMR15 and 49-53% overall yield over four steps.
Similarly, we were able to start with alcohol 716 (Scheme
2), producing 6b,e in >90% purity as judged by 1H NMR15
1
Figure 1. (a) DEPT spectrum (129-110 ppm) of 10 before RCM.
(b) Crude DEPT spectrum (129-110 ppm) of 11. Both 10 and 11
were derived from 7.
CH2 of the allyl group. After RCM, the spectrum of the crude
reaction mixture showed that the peak at 117.1 ppm had com-
pletely disappeared, and a new peak at 113.5 ppm had ap-
peared (Figure 1b). The peak at 113.5 ppm corresponds to
the styrene that is evolved during the RCM reaction.
Consequently, after precipitation and isolation of the met-
athesized oligomer, the peak at 113.5 ppm was not present.
In conclusion, we have shown that ROMpt provides an
integrated platform for accomplishing functional group
protection, phase-trafficking-induced purification of inter-
mediates, downstream soluble-supported synthesis, and
chemospecific release of final products. The load capacity
of the soluble supports is high and the cleaved support is
easily separated from the product by simple precipitation with
MeOH. Additionally, we have demonstrated that RCM
reactions can be accomplished with these ROM soluble
supports under typical RCM conditions, using only 10 mol
% catalyst.17 We feel that the robust nature of these soluble
Wang-type supports will be applicable to a wide range of
reaction sequences. We are currently pursuing the use of
these and other similar supports in ROMpt reaction se-
quences. These results will be reported in due course.
Scheme 2a
a Reagents and conditions: (a) (i) ClSO2NCO, CH2Cl2, 0 °C;
(ii) amino ester, Et3N, CH2Cl2, 60-87%. (b) (i) Cinnamyl alcohol,
PPh3, DIAD, THF, rt; (ii) 5 mol % (IMesH2)(PCy3)(Cl)2RudCHPh,
CH2Cl2, reflux; (iii) EtOCHdCH2; (iv) MeOH and then filter. (c)
Allyl bromide, K2CO3, NaI, DMF, 50 °C. (d) 10 mol %
(PCy3)2(Cl)2RudCHPh, CH2Cl2, 50 °C. (e) 1:1 TFA/CH2Cl2, 45-
55% over four steps.
Acknowledgment. This investigation was generously
supported by funds provided by the National Science Foun-
dation (NSF Career 9984926) and the National Institutes of
and 55 and 45% overall yields, respectively. The facile
production of 7 (two steps from commercially available
material) may lead to more widespread use compared to 1.
However, we have found that both 1 and 7 can be readily
prepared on a large scale.
(15) 1H NMR spectra of crude isolated products are available in
Supporting Information.
(16) For the synthesis of (()-7, see Supporting Information.
(17) For comparison, there are reports of performing RCM reactions on
the solid phase with as little as 10 mol % catalyst (see: (a) Pernerstorfer,
J.; Schuster, M.; Blechert, S. Synthesis 1999, 138-144. (b) Reichwein, J.
F.; Liskamp, R. M. J. Eur. J. Org. Chem. 2000, 2335-2344.); however,
loads of g30 mol % have also been reported (see: (c) Miller, S. J.;
Blackwell, H. E.; Grubbs, R. H. J. Am. Chem. Soc. 1996, 118, 9606-9614.
(d) Tang, Q.; Wareing, J. R. Tetrahedron Lett. 2001, 42, 1399-1401. (e)
Schmiedeberg, N.; Kessler, H. Org. Lett. 2002, 4, 59-62. (f) Koide, K.;
Finkelstein, J. M.; Ball, Z.; Verdine, G. L. J. Am. Chem. Soc. 2001, 123,
398-408).
It was found that the progress of the RCM could be
monitored by NMR analysis. Furthermore, the Wang-type
linker affords ample space to eliminate communication
between the stereocenters of the backbone and the amino
ester moiety, thus allowing for the acquisition of simplified
NMR spectra. Analysis of the DEPT spectrum of allylated
oligomer 10 (Figure 1a) revealed a single negative peak in
the olefin region at 117.1 ppm corresponding to the terminal
Org. Lett., Vol. 5, No. 1, 2003
17

Health (National Institute of General Medical Sciences, RO1-
GM58103) as well as an NIH Dynamic Aspects in Chemical
Biology Training Grant for A.M.H. The authors also thank
Materia, Inc., for many helpful discussions. Figure 1 was
generated using MestRe-C 2.3a, available through the
Internet at: http://qobrue.usc.es/jsgroup/MestRe-C/MestRe-
C.html.
Supporting Information Available: Details of the syn-
thesis of monomers 1 and 7 and experimental procedures
and characterization for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL0270327
18
Org. Lett., Vol. 5, No. 1, 2003